Process for the production of tetraaminobiphenol macrocyclic ligands; and novel tetraaminobiphenol macrocyclic ligands

ABSTRACT

A process for preparing a tetra-substituted aminobiphenol macrocyclic ligand having the structure (I), including the step of treating a precursor compound having the structure (II) with a compound having the structure R6-L where L is a leaving group (hereafter compound (III)) in the presence of a base.

TECHNICAL FIELD AND BACKGROUND

The present invention relates to an improved process for the productionof tetraaminobiphenol macrocyclic ligands, in particular,tetraaminobiphenol macrocyclic ligands for use in the production ofbimetallic catalysts employed in copolymerization reactions.

The invention relates in particular to an improved process for theproduction of tetraaminobiphenol macrocyclic ligands in which each ofthe amino moieties of the macrocyclic ligand is substituted, for examplealkylated or allylated.

The invention further relates to novel tetraaminobiphenol macrocyclicligands.

It is disclosed in Hodgkin, Polymer Science: Part A: Polymer ChemistryEdition, Vol. 24, 3117-3127 (1986), that a Mannich reaction betweenp-cresol, and N,N′-dimethylethylenediamine and formaldehyde yielded atetramethylaminobiphenol macrocyclic ligand. The process is as shown inoutline below.

In this method there is no alkylation step carried out on themacrocyclic ligand and therefore no risk of alkylating the phenolmoieties. However, the process has disadvantages. The macrocycle isformed in low yields as a by-product to the linear polymeric productsthat were the target of Hodgkin et al. There is no indication that anyother macrocyclic product could be made; but if this method werepossible for different substituents of the amine groups it would benecessary to run a new Mannich reaction for each macrocyclic ligand.

Direct alkylation of a tetraaminobiphenol macrocyclic ligand isdescribed in Chen et al., CrystEngComm, 2013, 15, 5168-5178. In thisreference it is stated that a tetraaminobiphenol macrocyclic ligand (3mmol) was reacted with ethylchloroacetate (6 mmol) and potassiumcarbonate (24 mmol) in dimethylformamide under reflux for 20 hours.Following filtration and evaporation the residue was hydrolysed withsodium hydroxide to give the desired tetracarboxylic acid ligand. Thereaction scheme is shown in outline below:

It is stated in the Chen reference that the tetracarboxyaminobiphenolligand H₆L was obtained in 65% yield. However this yield is notpossible: only two equivalents of ethylchloroacetate were used, per oneequivalent of the tetraaminobiphenol macrocyclic ligand H₂L′. It will beappreciated that the tetraaminobiphenol macrocyclic ligand of interestin the Chen reference has four N-sites and two phenolic moieties, all ofwhich are potential sites for reaction. Thus the theoretical maximum ofthe yield of the tetracarboxyaminobiphenol ligand is 50%; and this wouldassume no other products; for example no mono-carboxy ligand, nodi-carboxyaminobiphenol ligand, no tri-carboxyaminobiphenol ligand, andno alkylated phenol ligands of any sort. It may be noted here thatalkylation of phenol moieties under basic conditions is commonplace andis described in chemistry textbook. One literature example (from many)is Facile Synthesis of Alkyl Phenyl Ethers Using Cesium Carbonate, Leeet al, Synthetic Communications, 25(9), 13671370 (1995) which describesa “highly efficient” alkylation method of phenols using alkylhalides/cesium carbonate/acetonitrile.

For Chen to choose to use such a low amount of the alkylating agent—twomole equivalents when the target product has 4 moles of the carboxylatesubstituent—may indicate a desire to avoid competing reactions, such asalkylation of the phenol groups.

DETAILED DESCRIPTION

In accordance with a first aspect of the present invention there isprovided a process for preparing a tetra-substituted aminobiphenolmacrocyclic ligand having the structure (I), comprising the step oftreating a precursor compound having the structure (II) with a compoundhaving the structure R₆-L where L represents a leaving group(hereinafter compound (III)) in the presence of a base;

wherein R₁ and R₂ are independently selected from hydrogen, halide, anitro group, a nitrile group, an imine group, —NCR₁₃R₁₄, an amine, anether group —OR₁₅ or —R₁₆OR₁₇, an ester group —OC(O)R₁₀ or —C(O)OR₁₀, anamido group —NR₉C(O)R₉ or —C(O)—NR₉(R₉), —COOH, —C(O)R₁₅,—OP(O)(OR₁₈)(OR₁₉), —P(O)R₂₀R₂₁, a silyl group, a silyl ether group, asulfoxide group, a sulfonyl group, a sulfinate group or an acetylidegroup or an optionally substituted alkyl, alkenyl, alkynyl, haloalkyl,aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, alicyclic orheteroalicyclic group;R₃ is independently selected from optionally substituted alkylene,alkenylene, alkynylene, heteroalkylene, heteroalkenylene,heteroalkynylene, arylene, heteroarylene or cycloalkylene, whereinalkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene andheteroalkynylene, in each case optionally interrupted by aryl,heteroaryl, alicyclic or heteroalicyclic;R₄ is independently selected from hydrogen, or optionally substitutedaliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl,heteroaryl, alkylheteroaryl or alkylaryl;R₅ is independently selected from hydrogen, optionally substitutedaliphatic, heteroaliphatic, alicyclic, alkanoate, acrylate, carboxyl,heteroalicyclic, aryl, heteroaryl, alkylheteroaryl or alkylaryl, or twoR5 species may together be selected from optionally substitutedalkylene, alkenylene or alkynylene,bonded to two different N groups of the compound of structure (II),with the proviso that at least one of the species R₅ is hydrogen;and E is independently selected from NR₅ and NR₆, with the proviso thatat least one of the species E is NR₆;wherein R₆ is independently selected from optionally substitutedaliphatic, alicyclic, heteroalicyclic, aryl, heteroaryl, ether,polyether, or optionally substituted alkylaryl or alkylheteroaryl; andwherein R₉, R₁₀, R₁₃, R₁₄, R₁₈, R₁₉, R₂₀ and R₂₁ are independentlyselected from hydrogen or an optionally substituted aliphatic,heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl groupand R₁₅, R₁₆ and R₁₇ are independently selected from an optionallysubstituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, arylor heteroaryl group;wherein the molar ratio of compound of structure (III) to the number ofNH sites in the compound of structure (II) is at least 0.6.

Preferably the molar ratio of the compound having the structure (III) tospecies R₅ which are hydrogen in the compound having the macrocycle(II)—i.e. the number of NH sites in the macrocycle—is at least 0.8.

Preferably the molar ratio of the compound having the structure (III) tothe number of NH sites in the macrocycle (II) is at least 1.

In especially preferred embodiments the molar ratio of the compoundhaving the structure (III) to the number of NH sites in the macrocycle(II) is at least 1.1.

In a preferred process of the present invention the molar ratio of thecompound having the structure (III) to the number of NH sites in themacrocycle (II) is not greater than 2; preferably not greater than 1.6;preferably not greater than 1.4.

The number of NH sites in the macrocycle (II)′ may alternatively bereferred to as ‘the species R₅ which are hydrogen in compound (II)’.

In preferred embodiments the molar ratio of the compound of structure(III) to the compound of structure (II) is at least 2.2, preferably atleast 2.4.

One sub-group of compounds having the structure (IIa) shown below (andconforming to the more general structure (II)) has a single group R₅which is hydrogen and the remaining three groups R₅ which are any of thegroups mentioned above, but not hydrogen. In this subgroup the molarratio of the compound having the structure (III) to the compound ofstructure (IIa) is at least 0.6, preferably at least 0.8, morepreferably at least 1, and in especially preferred embodiments at least1.1. In the sub-group of compounds having the structure (IIa) the molarratio of the compound having the structure (III) to the compound ofstructure (IIa) is preferably not greater than 2; preferably not greaterthan 1.6; preferably not greater than 1.4.

One sub-group of compounds having the structure (IIb) shown below (andconforming to the more general structure (II)) has two groups R₅ whichare hydrogen and the remaining two groups R₅ which are any of the groupsmentioned above, but not hydrogen. In this subgroup the molar ratio ofthe compound having the structure (III) to the compound of structure(IIb) is at least 1.2, preferably at least 1.6, more preferably at least2, and in especially preferred embodiments at least 2.2. In thesub-group of compounds having the structure (IIb) the molar ratio of thecompound having the structure (III) to the compound of structure (IIb)is preferably not greater than 4; preferably not greater than 3.2;preferably not greater than 2.8.

One sub-group of compounds having the structure (IIc) shown below (andconforming to the more general structure (II)) has three group R₅ whichare hydrogen and the remaining single group R₅ which is any of thegroups mentioned above, but not hydrogen. In this subgroup the molarratio of the compound having the structure (III) to the compound ofstructure (IIc) is at least 1.8, preferably at least 2.4, morepreferably at least 3, and in especially preferred embodiments at least3.3. In the sub-group of compounds having the structure (IIc) the molarratio of the compound having the structure (III) to the compound ofstructure (IIc) is preferably not greater than 6; preferably not greaterthan 4.8; preferably not greater than 4.2.

One preferred sub-group of compounds having the structure (IId) shownbelow and (conforming to the more general structure (II)) has all fourgroups R₅ which are hydrogen. In this subgroup the molar ratio of thecompound having the structure (III) to the compound of structure (IId)is at least 2.4, preferably at least 3.2, preferably at least 3.6, morepreferably at least 4, more preferably at least 4.2, and in especiallypreferred embodiments at least 4.4. In the sub-group of compounds havingthe structure (IId) the molar ratio of the compound having the structure(III) to the compound of structure (IId) is preferably not greater than8; preferably not greater than 6.4; preferably not greater than 5.6.

The process of the present invention uses a significantly higher molarratio of compound (III) to species R₅ which are hydrogen in compound(II), compared with the prior art of Chen, mentioned above. In Chen'spublication the molar ratio of the chloroethylacetate to the fouralkylatable NH groups on the ligand H₂L′ is 0.5.

Surprisingly, the present inventors have found that very high yields ofthe target substituted aminobiphenol ligands of formula I can beobtained, despite the presence of the phenol sites at which reactionmight be expected, and use of a high molar ratio of reactant (III). Tothe inventors' surprise, the use of such a high mole ratio of thereactant (III) does not appear to promote competing reactions at thephenolic —OH sites. Rather, it produces the compound of formula (I) inhigh yield and at high selectivity.

Each of the occurrences of the groups R₁ and R₂ may be the same ordifferent. Preferably, R₁ and R₂ are independently selected fromhydrogen, halide, amino, nitro, sulfoxide, sulfonyl, sulfinate, silyl,silyl ether and an optionally substituted alkyl, alkenyl, aryl,heteroaryl, heteroalicyclic, alkoxy, aryloxy or alkylthio. Preferably,each occurrence of R₂ is the same, and is hydrogen or alkyl, for examplemethyl. Preferably R₂ is hydrogen.

Even more preferably, R₂ is alkyl or, especially, hydrogen, and R₁ isindependently selected from hydrogen, halide, amino, nitro, sulfoxide,sulfonyl, sulfinate, silyl, silyl ether and optionally substitutedalkyl, alkenyl, aryl, heteroaryl, heteroalicyclic, alkoxy, aryloxy,alkylthio or arylthio, such as hydrogen, C₁₋₆alkyl (e.g. haloalkyl),alkoxy, aryl, halide, nitro, sulfonyl, silyl and alkylthio, for examplet-butyl, n-butyl, i-propyl, methyl, piperidinyl, methoxy, hexyl methylether, —SCH₃, —S(C₆H₅), H, nitro, trimethylsilyl, methylsulfonyl(—SO₂CH₃), triethylsilyl, halogen or phenyl.

Each occurrence of R₁ can be the same or different, and R₁ and R₂ can bethe same or different. Preferably each occurrence of R₁ is the same.Preferably each occurrence of R₂ is the same. When R₁ and R₂ are thesame, preferably each occurrence of R₁ and R₂ is hydrogen or methyl.Preferably, each occurrence of R₁ is the same, and each occurrence of R₂is the same, and R₁ is different to R₂.

Preferably both occurrences of R₁ are the same, and are selected fromhydrogen, halide, amino, nitro, sulfoxide, sulfonyl, sulfinate, silyl,silyl ether and an optionally substituted alkyl, alkenyl, aryl,heteroaryl, heteroalicyclic, alkoxy, aryloxy, or alkylthio. Morepreferably both occurrences of R₁ are the same, and are selected fromhalide, sulfoxide, silyl, and an optionally substituted alkyl,heteroaryl or alkoxy. Still more preferably both occurrences of R₁ arethe same, and are selected from H, alkyl, aryl, alkoxy, trialkylsilylsuch as triethylsilyl, or halide. More preferably still both occurrencesof R₁ are the same, and are selected from H, alkyl, phenyl, halide ortrialkylsilyl. Most preferably, both occurrences of R₁ are the same, andare selected from H, methyl, ethyl, n-propyl, i-propyl n-butyl, t-butyl,t-amyl, t-octyl, methylthio, methoxy and triethylsilyl.

It will be appreciated that the group R₃ can be the divalent alkylene,alkenylene, alkynylene, heteroalkylene, heteroalkenylene orheteroalkynylene group which may optionally be interrupted by an aryl,heteroaryl, alicyclic or heteroalicyclic group, or may be a divalentarylene or cycloalkylene group which acts as a bridging group betweentwo nitrogen centres in the macrocycle of formula (I). Thus, where R₃ isan alkylene group, such as 2,2-dimethylpropane-1,3-diyl, the R₃ grouphas the structure —CH₂—C(CH₃)₂—CH₂—. The definitions of the alkyl, aryl,cycloalkyl etc groups set out herein therefore also relate respectivelyto the divalent alkylene, arylene, cycloalkylene etc groups set out forR₃, and may also be optionally substituted. Exemplary options for R₃include ethane-1,2-diyl, 2,2-fluoropropane-1,3-diyl,2,2-dimethylpropane-1,3-diyl, propane-1,3-diyl, butane-1,4-diyl,phenylene, cyclohexane-1,4-diyl, cyclohexane-1,2-diyl or biphenylene.When R₃ is cyclohexane-1,4-diyl or cyclohexane-1,2-diyl, it can be theracemic, RR- or SS-forms.

R₃ can be independently selected from substituted or unsubstitutedalkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene orheteroalkynylene, arylene or cycloalkylene. Preferably, R₃ is selectedfrom substituted or unsubstituted alkylene, cycloalkylene, alkenylene,heteroalkylene and arylene. More preferably, R₃ is selected from—CH₂C(CH₃)₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂C(CH₂C₆H₅)₂CH₂—,—(C₆H₄)—, —CH₂CH₂—, —CH₂—CH₂CH₂CH₂—, —CH₂CH₂N(CH₃)CH₂CH₂—, —(C₆H₁₀)— or—CH₂CH₂CH(C₂H₅)—. Still more preferably R₃ is selected from—CH₂C(CH₃)₂CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—,—CH₂C(CH₂C₆H₅)₂CH₂—, —CH₂CH₂CH(C₂H₅)—, —CH₂CH₂CH₂CH₂—. More preferablystill, R₃ is selected from —CH₂C(CH₃)₂CH₂—, CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—and —CH₂C(C₂H₅)₂CH₂—.

R₃ can be independently selected from substituted or unsubstitutedalkylenes and substituted or unsubstituted arylenes, preferablysubstituted or unsubstituted propylenes, such as propane-1,3-diyl and2,2-dimethylpropane-1,3-diyl, and substituted or unsubstituted phenyleneor biphenylene. Preferably both occurrences of R₃ are the same. Evenmore preferably R₃ is a substituted propane-1,3-diyl, such as2,2-di(alkyl)propane-1,3-diyl, especially 2,2-dimethylpropane-1,3-diyl.

Preferably, each R₄ is independently selected from hydrogen, andoptionally substituted aliphatic or aryl. More preferably, each R₄ isindependently selected from hydrogen, and optionally substituted alkylor aryl. Even more preferably, each R₄ is the same, and is selected fromhydrogen, and optionally substituted alkyl or aryl. Exemplary R₄ groupsinclude hydrogen, methyl, ethyl, n-propyl, n-butyl, phenyl andtrifluoromethyl, preferably hydrogen, methyl or trifluoromethyl. Evenmore preferably, each R₄ is hydrogen.

In preferred combinations of the R₄ group and R₁ group, R₁ is selectedfrom H, methyl, ethyl, n-propyl, n-butyl, t-butyl, t-octyl, Cl, Br, F,nitro, trimethylsilyl, triethylsilyl, methoxy or methylthio and R₄ isselected from H, methyl, ethyl, n-propyl, phenyl, trifluoromethyl.

Preferably R₅ is independently selected from hydrogen, optionallysubstituted aliphatic, heteroaliphatic, alicyclic, alkanoate, acrylate,carboxyl, heteroalicyclic, aryl, heteroaryl, alkylheteroaryl oralkylaryl; or two R5 groups may together be an optionally substitutedalkylene group, for example a C(1-10alkylene) group optionallysubstituted by an optionally substituted aryl group. At least onespecies R₅ is hydrogen. In embodiments of the invention one, two, threeor four species R₅ may be hydrogen, as shown in structures (IIa)-(IId)above. Species NR₅ which are NH provide a site or sites for reaction ofthe compound of structure (III) and introduction of the species R₆. Thusan NH species in the compound of structure (II) can provide the site foran NR₆ species in the compound of structure (I).

Preferably R₅ is independently selected from hydrogen, optionallysubstituted alkyl which is optionally interrupted by at least one Natom, or by at least one O atom, or by at least one S atom, optionallysubstituted alkylthio, alkylaryl, alkylheteroaryl, alkenyl, alkynyl,heteroalkenyl, heteroalkynyl, aryl, heteroaryl, alicyclic,heteroalicyclic, sulfonate, alkanoate (—C(O)—OR₁₀), carbonyl(—C(O)—R₁₀), ether or, polyether, acrylate, or carboxyl. More preferredR₅ species include optionally substituted groups selected from alkyl(such as methyl, ethyl, propyl, butyl), alkylaryl, alkylheteroaryl (suchas benzyl, substituted benzyl or methyl pyridine), alkenyl (such asallyl), alkynyl (such as propargyl), sulfonate (such as tosylate),alkanoate (such as —C(O)—O-t-butyl (BOC), —C(O)—O-benzyl,—C(O)—O-9-fluorenylmethyl (FMOC)), and optionally substitutedaryl-C(O)OR₁₀, alkylaryl-C(O)OR₁₀, alkyl-C(O)—OR₁₀ (such as—CH₂—C(O)—OMe, —CH₂CH₂—C(O)—OMe) or alkyl-C≡N (such as —CH₂CH₂—C≡N).Most preferred species R₅ include methyl, ethyl, propyl (preferablyn-propyl), butyl (preferably n-butyl), allyl, propargyl, benzyl,4-nitrobenzyl, —CH₂CH₂—C(O)—OR₁₀, —CH₂CH₂—C≡N. or —C(1-4)alkylC(O)O—,for example, acetate or propanoate, or optionally substitutedalkylarylC(O)O— or arylC(O)O—, for example benzoate which isunsubstituted or ring-substituted by 1, 2 or 3 C(1-4)alkyl groups. Itwill be appreciated that some of the groups defined above will beassociated with a cation. The cation will typically be a sodium, lithiumor ammonium cation.

When there is a plurality of groups R₅ which are not hydrogen, suchgroups may be identical or they may all differ from each other.

In some embodiments two R₅ species are together selected from methylene—CH₂—, ethylene —CH₂—CH₂—, propylene —CH₂—CH₂—CH₂— or phenylmethylene—CH(Ph)-, bonded to two different N groups of the compound of structure(II).

Preferably each R₆ is independently selected from optionally substitutedaliphatic, alicyclic, heteroalicyclic, aryl, heteroaryl, ether,polyether, or optionally substituted alkylaryl or alkylheteroaryl. Morepreferably, each R₆ is independently selected from optionallysubstituted alkyl (such as methyl, ethyl, propyl, butyl), alicyclic(such as cyclohexane), alkenyl (such as allyl), alkynyl (such aspropargyl) or alkylaryl (such as benzyl, substituted benzyl,methylpyridine, ether (such as methoxymethyl), polyether (such aspolyethylene glycol (PEG), polypropylene glycol (PPG), Preferred R₆groups include C(1-10)alkyl, preferably C(1-6)alkyl, more preferablyC(1-4)alkyl, most preferably methyl, ethyl, n-propyl, n-butyl; or allylor propargyl or benzyl.

In preferred combinations of the R₆ group and R₁ group, R₁ is selectedfrom H, methyl, ethyl, n-propyl, n-butyl, t-butyl, t-octyl, C, Br, F,nitro, trimethylsilyl, triethylsilyl, methoxy or methylthio and R₆ isselected from methyl, ethyl, n-propyl, n-butyl, allyl and benzyl.

When there is a plurality of groups R₆ such groups are preferablyidentical.

Preferably each R₅ group is different from each R₆ group.

The compound having the structure (III) introduces groups R₆ to providethe compound of formula (I). The leaving group L of the compound havingthe structure (III) is preferably selected from halogen, for example:chloro, bromo or iodo; or an ether group (for example when the compoundR₆-L is a trialkyloxonium compound); or a tertiary amine (for examplewhen the compound R₆-L is a quaternary ammonium salt, for example atetraalkyl ammonium salt; or a sulfonate group of formula —O—SO₂—R_(x)where R_(x) is selected from optionally substituted aliphatic or aryl oralkaryl; for example an alkyl sulfonate, aryl sulfonate, halo sulfonateor trifluoroalkyl sulfonate, for example tosylate, mesylate, triflate,fluorosulfonate, nosylate or brosylate; or a group of formula—O—SO₂—O—R_(y) or —O—CO—O—R_(y) where R_(y) represents optionallysubstituted aliphatic or aryl or alkaryl, preferably an alkyl group, forexample methyl and ethyl. Sulfonate compounds suitable for use in thepresent invention may be polymer-bound, for example on polystyrene. Whenthe leaving group L is of formula —O—SO₂—O—R_(y) or —O—CO—O—R_(y) it ispreferred that R₆ and R_(y) are identical. Preferably they are bothC₍₁₋₄₎ alkyl groups, preferably both methyl or both ethyl.

A base for use in the process of the first aspect may be an inorganicbase or an organic base. Preferred inorganic bases include metalcompounds, for example of Group 1 and Group II metals. Preferred metalcompounds are carbonates, hydrogen carbonates, alkanoates, hydroxides,silicates, phosphates and borates. Preferred cationic species thereofare Group 1 metals, most preferably sodium, potassium or cesium; GroupII metals, preferably magnesium, calcium, strontium and barium; orammonium. Preferred anionic species of the metal compounds are (C1-4)alkanoates (especially acetates), carbonates, and hydroxides. Preferredbases include sodium carbonate, potassium carbonate, cesium carbonate,magnesium carbonate, calcium carbonate, ammonium carbonate, sodiumhydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide,ammonium hydroxide, sodium (C1-10) alkanoates, preferably sodium (C1-4)alkanoates, especially sodium acetate, potassium alkanoates, preferablypotassium (C1-4) alkanoates, especially potassium acetate, sodiummetasilicate, potassium metasilicate, sodium borate, potassium borate,trisodium phosphate, disodium phosphate, monosodium phosphate,monopotassium phosphate, dipotassium phosphate and tripotassiumphosphate. Especially preferred bases are sodium carbonate, potassiumcarbonate, sodium acetate, potassium acetate, mono-, di- or trisodiumphosphate, mono-, di- or tripotassium phosphate, sodium hydroxide orpotassium hydroxide.

Preferred organic bases include tertiary amine bases, suitably carryinggroups selected from alkyl and alkylene. Preferably tertiary alkylaminebases have from 1 to 3 amine groups and C(1-10) alkyl or C(1-10)alkylene groups in place of all N-hydrogen species. Preferred tertiaryalkylamine bases are of formula (C1-10alkyl)₃-N, especiallytriethylamine, tripropylamine, tributylamine, tri-isobutylamine ordiisopropylethylamine. Preferred organic bases may further includetrialkanolamine bases, especially triethanolamine.

A preferred base for use in the process of the invention has a pKb inthe range from −2 to 14 when in an aqueous solution. It will beunderstood that the process of the present invention need not employaqueous conditions and therefore that the pKb of the base does notrepresent any measurable pKb under the reaction conditions. Rather it isused a representation of the strength of the base and it is believed toprovide a useful guide to bases which are suitable for use in thepresent invention. In preferred embodiments the pKb in the range atleast 0 (zero) to less than 13.5. Preferably the base has a pKb of atleast 0, preferably at least 0.5, preferably at least 1, more preferablyat least 2, more preferably at least 3. Preferably it has a pKb of notgreater than 13, preferably not greater than 12, more preferably notgreater than 10.

The process of the present invention may take place in the presence of asolvent. However in embodiments of the invention the reactants describedabove, in particular the compound of structure (III) and/or the base,may function as the solvent, and no further solvent is employed.

When a solvent is employed (in addition to the reactant species), it maysuitably be selected from substituted alkyl, optionally substitutedalkanol (especially halogenated alkanol; suitable halogen atoms beingchlorine, bromine and iodine), a cyclic ether, an aliphatic ether, adialkylformamide, a ketone, an ester, a dialkyl sulfoxide, an alkylnitrile optionally substituted aryl; or optionally substitutedheteroaryl. Water may also be used in some embodiments. A single solventor a mixture of solvents may be used.

Preferred solvents have up to 20 carbon atoms, preferably up to 12carbon atoms, preferably up to 8 carbon atoms.

Preferred substituted alkyl groups include halo C(1-4)alkyl groups,preferably chloro (C1-4)alkyl groups, for example chloroform ordichloromethane.

Preferred alkanols and haloalkanols are methanol, ethanol, propanol,iso-propanol, iso-butanol, t-butyl alcohol, phenol, n-butanol andchlorocapryl alcohol. Especially preferred alkanols are methanol andethanol. A particularly preferred alkanol is methanol.

Preferred cyclic ethers are optionally substituted cycloaliphaticcompounds having from 5-8 ring atoms of which at least one ring atom isan oxygen atom. Preferred substituents are one or two C(1-4) alkylgroups. Examples of suitable cyclic ethers include tetrahydrofuran,C(1-4)alkyl-substituted tetrahydrofurans, for example 2-methyltetrahydrofuran, dioxane and dioxolane.

Preferred aliphatic ethers include simple ethers, for example alkyleneinterrupted by one or more oxygen atoms, being for example ethers offormula R—O—R where each R represents an alkyl group; or may be glycols,glycol ethers and dialkyl glycols. Preferred simple ethers have theformula C(1-6)alkyl-O—C(1-6)alkyl, for example dibutyl ether. Preferredglycols have the formula HO—C(1-6)alkyl-OH. Preferred glycol ethers havethe formula C(1-6)alkyl-O—C(1-6)alkyl-OH. Preferred dialkyl glycols havethe formula C(1-6)alkyl-O—C(1-6)alkyl-O—C(1-6)alkyl, for exampledimethyoxyethane.

Preferred alkyl nitriles are C(1-10)alkyl nitriles, preferablyC(1-4)alkyl nitriles, for example acetonitrile.

Preferred dialkylformamides are di-C(1-10)alkyl formamides, preferablyC(1-4)alkyl formamides, for example dimethyl formamide.

Preferred ketones are diC(1-10)alkyl ketones, preferably di(C(1-4)alkylketones, for example acetone.

Preferred esters are C(1-10)alkanoate esters, for example C(1-4)alkylC(1-4) alkanoate esters, for example ethyl acetate.

Preferred dialkyl sulfoxides are di-C(1-10)alkyl sulfoxides, preferablydi-C(1-4)alkyl sulfoxides, for example dimethyl sulfoxide.

Preferred optionally substituted aryl groups include benzene substitutedby 1-3 (C(1-4) alkyl groups.

Especially preferred alkylbenzene solvents include toluene, xylene andethylbenzene.

A preferred optionally substituted heteroaryl group is pyridine.

Preferably, the process of the present invention is carried out at atemperature in the range 0 to 100° C., more preferably between 20 to 80°C. Some preferred embodiments are carried out at ambient temperature.Other preferred embodiments are carried out at the reflux temperature ofthe reaction system.

In a preferred process of the present invention the molar ratio of thebase to the precursor compound having the structure (II) is at least 1;preferably at least 2; in some embodiments it is preferably at least 4;preferably at least 5.

In a preferred process of the present invention the molar ratio of thebase to the precursor compound having the structure (II) is not greaterthan 7.5; preferably not greater than 6.

Preferably the molar ratio of the base to the number of NH sites in thecompound of structure (II) is from 1 to 1.9, preferably from 1.1 to 1.8,and most preferably from 1.25 to 1.75.

Biphenol ligand precursors having the structure (II) used in the presentinvention and having four NH groups in the macrocyclic ring aredescribed in publically available sources; for example in WO2016/012785and in Chen et al., CrystEngComm, 2013, 15, 5168-5178, described above.

Biphenol ligand precursors having the structure (II) used in the presentinvention and having one, two or three NH groups in the macrocyclic ring(the other N atom having a substituent) may be prepared using protectinggroup chemistry in the absence of a base, as described in WO2016/012785.Alternative methods are described in Hodgkin, Polymer Science: Part A:Polymer Chemistry Edition, Vol. 24, 3117-3127 (1986), mentioned above.

Preferably the process of the present invention does not employ aprotecting group protecting the phenol moieties. Surprisingly, it hasbeen found that the process proceeds in high yield to thetetrasubstituted amino product of formula (I) even without suchprotection. In preferred embodiments of the invention yields of greaterthan 50% of the tetrasubstituted amino product of formula (I) areachieved, even without such protection. In preferred examplessubstantially higher yields have been obtained.

In the process of the invention the base may be dissolved in thereaction system. The base may be completely dissolved already at thestart of the reaction. Alternatively the base may be heterogeneous, ormay be partially dissolved, but able to accept protons as the reactionproceeds.

In accordance with a second aspect of the invention there is provided acompound of structure (Ie)

wherein R₁ and R₂ are independently selected from hydrogen, halide, anitro group, a nitrile group, an imine group, —NCR₁₃R₁₄, an amine, anether group —OR₁₅ or —R₁₆OR₁₇, an ester group —OC(O)R₁₀ or —C(O)OR₁₀, anamido group —NR₉C(O)R₉ or —C(O)—NR₉(R₉), —COOH, —C(O)R₁₅,—OP(O)(OR₁₈)(OR₁₉), —P(O)R₂₀R₂₁, a silyl group, a silyl ether group, asulfoxide group, a sulfonyl group, a sulfinate group or an acetylidegroup or an optionally substituted alkyl, alkenyl, alkynyl, haloalkyl,aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, alicyclic orheteroalicyclic group;R₃ is independently selected from optionally substituted alkylene,alkenylene, alkynylene, heteroalkylene, heteroalkenylene,heteroalkynylene, arylene, heteroarylene or cycloalkylene, whereinalkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene andheteroalkynylene, in each case optionally interrupted by aryl,heteroaryl, alicyclic or heteroalicyclic;R₄ is independently selected from hydrogen, or optionally substitutedaliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl,heteroaryl, alkylheteroaryl or alkylaryl;and E is independently selected from NR′₅ and NR₆,wherein R′₅ is independently selected from hydrogen, optionallysubstituted aliphatic, heteroaliphatic, alicyclic, alkanoate, acrylate,carboxyl, heteroalicyclic, aryl, heteroaryl, alkylheteroaryl oralkylaryl;or two R₅ species may together be selected from optionally substitutedalkylene, alkenylene or alkynylene, bonded to two different N groups ofthe compound of structure (II);wherein R₆ is independently selected from optionally substitutedaliphatic, alicyclic, heteroalicyclic, aryl, heteroaryl, ether,polyether, or optionally substituted alkylaryl or alkylheteroaryl;with the first proviso that at least one of the species E conforms tothe definition given for NR₆;and with the second proviso that the groups R′₅ and R₆ are not allidentical with each other.wherein R₉, R₁₀, R₁₃, R₁₄, R₁₈, R₁₉, R₂₀ and R₂₁ are independentlyselected from hydrogen or an optionally substituted aliphatic,heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl groupand R₁₅, R₁₆ and R₁₇ are independently selected from an optionallysubstituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, arylor heteroaryl group.

Thus these compounds of structure (Ie) are asymmetrical as regards theirgroups R′₅ and R₆.

In this aspect of the invention R₁, R₂, R₃, R₄, R₅, R₆, R₉, R₁₀, R₁₃,R₁₄, R₁₈, R₁₉, R₂₀ and R₂₁ may be as defined in any statement or claimcontained in this specification. R′₅ may be as defined about for R₅,except that it cannot be hydrogen.

It is the process of the first aspect that enables these compounds ofstructure (Ie). In the process the NH group or groups in the macrocycleof structure (II) are replaced on introduction of group(s) R₆; whilstN-substituent group or groups already on the macrocycle (II) remain. Thegroups on the macrocycle, designated R′₅ and R₆ in the definition of thecompounds (Ie), can be selected to be non-identical. Thus asymmetricalcompounds of structure (Ie) may be provided.

Definitions

For the purpose of the present invention, an aliphatic group is ahydrocarbon moiety that may be straight chain or branched and may becompletely saturated, or contain one or more units of unsaturation, butwhich is not aromatic. The term “unsaturated” means a moiety that hasone or more double and/or triple bonds. The term “aliphatic” istherefore intended to encompass alkyl, alkenyl or alkynyl groupsincluding multivalent equivalents such as alkylene, alkenylene andalkynylene, and combinations thereof. An aliphatic group is preferably aC₁₋₂₀ aliphatic group, that is, an aliphatic group with 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.Preferably, an aliphatic group is a C₁₋₁₅ aliphatic, more preferably aC₁₋₁₂ aliphatic, more preferably a C₁₋₁₀ aliphatic, even more preferablya C₁₋₈ aliphatic, such as a C₁₋₆ aliphatic group.

An alkyl group is preferably a “C₁₋₂₀ alkyl group”, that is an alkylgroup that is a straight or branched chain with 1 to 20 carbons. Thealkyl group therefore has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19 or 20 carbon atoms. Preferably, an alkyl group is aC₁₋₁₅ alkyl, preferably a C₁₋₁₂ alkyl, more preferably a C₁₋₁₀ alkyl,even more preferably a C₁₋₈ alkyl, even more preferably a C₁₋₆ alkylgroup. Specifically, examples of “C₁₋₂₀ alkyl group” include methylgroup, ethyl group, n-propyl group, iso-propyl group, n-butyl group,iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group,n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decylgroup, n-undecyl group, n-dodecyl group, n-tridecyl group, n-tetradecylgroup, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group,n-octadecyl group, n-nonadecyl group, n-eicosyl group,1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropylgroup, 1-ethylpropyl group, n-hexyl group, 1-ethyl-2-methylpropyl group,1,1,2-trimethylpropyl group, 1-ethylbutyl group, 1-methylbutyl group,2-methylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group,2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutylgroup, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl groupand the like.

Alkenyl and alkynyl groups are preferably “C₂₋₂₀ alkenyl” and “C₂₋₂₀alkynyl”, more preferably “C₂₋₁₅ alkenyl” and “C₂₋₁₅ alkynyl”, even morepreferably “C₂₋₁₂ alkenyl” and “C₂₋₁₂ alkynyl”, even more preferably“C₂₋₁₀ alkenyl” and “C₂₋₁₀ alkynyl”, even more preferably “C₂₋₈ alkenyl”and “C₂₋₈ alkynyl”, most preferably “C₂₋₆ alkenyl” and “C₂₋₆alkynyl”groups, respectively.

Alkylene is divalent but otherwise defined as an alkyl group above.Likewise, alkenylene and alkynylene are defined as divalent equivalentsof alkenyl and alkynyl above.

A heteroaliphatic group (including heteroalkyl, heteroalkenyl andheteroalkynyl) is an aliphatic group as described above, whichadditionally contains one or more heteroatoms. Heteroaliphatic groupstherefore preferably contain from 2 to 21 atoms, preferably from 2 to 16atoms, more preferably from 2 to 13 atoms, more preferably from 2 to 11atoms, more preferably from 2 to 9 atoms, even more preferably from 2 to7 atoms, wherein at least one atom is a carbon atom. Particularlypreferred heteroatoms are selected from O, S, N, P and Si. Whenheteroaliphatic groups have two or more heteroatoms, the heteroatoms maybe the same or different.

Heteroalkylene is divalent but otherwise defined as a heteroalkyl groupabove. Likewise, heteroalkenylene and heteroalkynylene are defined asdivalent equivalents of heteroalkenyl and heteroalkynyl above. Analicyclic group is a saturated or partially unsaturated cyclic aliphaticmonocyclic or polycyclic (including fused, bridging and spiro-fused)ring system which has from 3 to 20 carbon atoms, that is an alicyclicgroup with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19or 20 carbon atoms. Preferably, an alicyclic group has from 3 to 15,more preferably from 3 to 12, even more preferably from 3 to 10, evenmore preferably from 3 to 8 carbon atoms, even more preferably from 3 to6 carbons atoms. The term “alicyclic” encompasses cycloalkyl,cycloalkenyl and cycloalkynyl groups. It will be appreciated that thealicyclic group may comprise an alicyclic ring bearing one or morelinking or non-linking alkyl substituents, such as —CH₂-cyclohexyl.Specifically, examples of the C₃₋₂₀ cycloalkyl group includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyland cyclooctyl.

A heteroalicyclic group is an alicyclic group as defined above whichhas, in addition to carbon atoms, one or more ring heteroatoms, whichare preferably selected from O, S, N, P and Si. Heteroalicyclic groupspreferably contain from one to four heteroatoms, which may be the sameor different. Heteroalicyclic groups preferably contain from 5 to 20atoms, more preferably from 5 to 14 atoms, even more preferably from 5to 12 atoms.

An aryl group is a monocyclic or polycyclic ring system having from 5 to20 carbon atoms. An aryl group is preferably a “C₆₋₁₂ aryl group” and isan aryl group constituted by 6, 7, 8, 9, 10, 11 or 12 carbon atoms andincludes condensed ring groups such as monocyclic ring group, orbicyclic ring group and the like. Specifically, examples of “C₆₋₁₀ arylgroup” include phenyl group, biphenyl group, indenyl group, naphthylgroup or azulenyl group and the like. It should be noted that condensedrings such as indan and tetrahydro naphthalene are also included in thearyl group.

A heteroaryl group is an aryl group having, in addition to carbon atoms,from one to four ring heteroatoms which are preferably selected from O,S, N, P and Si. A heteroaryl group preferably has from 5 to 20, morepreferably from 5 to 14 ring atoms. Specifically, examples of aheteroaryl group include pyridine, imidazole, methylimidazole anddimethylaminopyridine.

Examples of alicyclic, heteroalicyclic, aryl and heteroaryl groupsinclude but are not limited to cyclohexyl, phenyl, acridine,benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole,carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine,dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine,indole, indoline, indolizine, indazole, isoindole, isoquinoline,isoxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole,oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine,phenothiazine, phenoxazine, phthalazine, piperazine, piperidine,pteridine, purine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline,quinoline, quinoxaline, quinazoline, quinolizine, tetrahydrofuran,tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole,thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran,triazine, triazole, and trithiane.

Arylene is divalent but otherwise defined as an aryl group above.Likewise heteroarylene is defined as divalent equivalents of heteroaryland cycloalkylene as divalent equivalents of alicyclic andheteroalicyclic above.

The term “halide” or “halogen” or “halo” are used interchangeably and,as used herein mean a fluorine atom, a chlorine atom, a bromine atom, aniodine atom and the like, preferably a fluorine atom, a bromine atom ora chlorine atom, and more preferably a fluorine atom.

A haloalkyl group is preferably a “C₁₋₂₀ haloalkyl group”, morepreferably a “C₁₋₁₅ haloalkyl group”, more preferably a “C₁₋₁₂ haloalkylgroup”, more preferably a “C₁₋₁₀ haloalkyl group”, even more preferablya “C₁₋₈ haloalkyl group”, even more preferably a “C₁₋₆ haloalkyl group”and is a C₁₋₂₀ alkyl, a C₁₋₁₅ alkyl, a C₁₋₁₂ alkyl, a C₁₋₁₀ alkyl, aC₁₋₈ alkyl, or a C₁₋₆ alkyl group, respectively, as described abovesubstituted with at least one halogen atom, preferably 1, 2 or 3 halogenatom(s). Specifically, examples of “C₁₋₂₀ haloalkyl group” includefluoromethyl group, difluoromethyl group, trifluoromethyl group,fluoroethyl group, difluorethyl group, trifluoroethyl group,chloromethyl group, bromomethyl group, iodomethyl group and the like.

An alkoxy group is preferably a “C₁₋₂₀ alkoxy group”, more preferably a“C₁₋₁₅ alkoxy group”, more preferably a “C₁₋₁₂ alkoxy group”, morepreferably a “C₁₋₁₀ alkoxy group”, even more preferably a “C₁₋₈ alkoxygroup”, even more preferably a “C₁₋₆ alkoxy group” and is an oxy groupthat is bonded to the previously defined C₁₋₂₀ alkyl, C₁₋₁₅ alkyl, C₁₋₁₂alkyl, C₁₋₁₀ alkyl, C₁₋₈ alkyl, or C₁₋₆ alkyl group respectively.Specifically, examples of “C₁₋₂₀ alkoxy group” include methoxy group,ethoxy group, n-propoxy group, iso-propoxy group, n-butoxy group,iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxygroup, iso-pentyloxy group, sec-pentyloxy group, n-hexyloxy group,iso-hexyloxy group, n-hexyloxy group, n-heptyloxy group, n-octyloxygroup, n-nonyloxy group, n-decyloxy group, n-undecyloxy group,n-dodecyloxy group, n-tridecyloxy group, n-tetradecyloxy group,n-pentadecyloxy group, n-hexadecyloxy group, n-heptadecyloxy group,n-octadecyloxy group, n-nonadecyloxy group, n-eicosyloxy group,1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group,2,2-dimethylpropoxy group, 2-methylbutoxy group, 1-ethyl-2-methylpropoxygroup, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group,1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutoxygroup, 1,3-dimethylbutoxy group, 2-ethylbutoxy group, 2-methylpentyloxygroup, 3-methylpentyloxy group and the like.

An aryloxy group is preferably a “C₅₋₂₀ aryloxy group”, more preferablya “C₆₋₁₂ aryloxy group”, even more preferably a “C₆₋₁₀ aryloxy group”and is an oxy group that is bonded to the previously defined C₅₋₂₀ aryl,C₆₋₁₂ aryl, or C₆₋₁₀ aryl group respectively.

An alkylthio group is preferably a “C₁₋₂₀ alkylthio group”, morepreferably a “C₁₋₁₅ alkylthio group”, more preferably a “C₁₋₁₂ alkylthiogroup”, more preferably a “C₁₋₁₀ alkylthio group”, even more preferablya “C₁₋₈ alkylthio group”, even more preferably a “C₁₋₆ alkylthio group”and is a thio (—S—) group that is bonded to the previously defined C₁₋₂₀alkyl, C₁₋₁₅ alkyl, C₁₋₁₂ alkyl, C₁₋₁₀ alkyl, C₁₋₈ alkyl, or C₁₋₆ alkylgroup respectively. An alkylthio group utilised as a substituent asdefined herein, may be connected via either a carbon atom of the alkylgroup as defined above or the sulphur atom of the thio group. Anarylthio group is preferably a “C₅₋₂₀ arylthio group”, more preferably a“C₆₋₁₂ arylthio group”, even more preferably a “C₆₋₁₀ arylthio group”and is a thio (—S—) group that is bonded to the previously defined C₅₋₂₀aryl, C₆₋₁₂ aryl, or C₆₋₁₀ aryl group respectively.

An alkylaryl group is preferably a “C₆₋₁₂ aryl C₁₋₂₀ alkyl group”, morepreferably a preferably a “C₆₋₁₂ aryl C₁₋₁₆ alkyl group”, even morepreferably a “C₆₋₁₂ aryl C₁₋₆alkyl group” and is an aryl group asdefined above bonded at any position to an alkyl group as defined above.The point of attachment of the alkylaryl group to a molecule may be viathe alkyl portion and thus, preferably, the alkylaryl group is —CH₂-Phor —CH₂CH₂-Ph. An alkylaryl group can also be referred to as “aralkyl”.

A silyl group is preferably a group —Si(R_(s))₃, wherein each R_(s) canbe independently an aliphatic, heteroaliphatic, alicyclic,heteroalicyclic, aryl or heteroaryl group as defined above. In certainembodiments, each R_(s) is independently an unsubstituted aliphatic,alicyclic or aryl. Preferably, each R_(s) is an alkyl group selectedfrom methyl, ethyl or propyl.

A silyl ether group is preferably a group OSi(R₅)₃ wherein each R₅ canbe independently an aliphatic, heteroaliphatic, alicyclic,heteroalicyclic, aryl or heteroaryl group as defined above. In certainembodiments, each R₅ can be independently an unsubstituted aliphatic,alicyclic or aryl. Preferably, each R₅ is an optionally substitutedphenyl or optionally substituted alkyl group selected from methyl,ethyl, propyl or butyl (such as n-butyl or tert-butyl (tBu)). Exemplarysilyl ether groups include OSi(CH₃)₃, OSi(C₂H₅)₃, OSi(C₆H₅)₃,OSi(CH₃)₂(tBu), OSi(tBu)₃ and OSi(C₆H₅)₂(tBu).

A nitrile group (also referred to as a cyano group) is a group CN.

An imine group is a group —CR₆NR₆, preferably a group —CHNR₆ wherein R₆is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl orheteroaryl group as defined above. In certain embodiments, R₆ isunsubstituted aliphatic, alicyclic or aryl. Preferably R₆ is an alkylgroup selected from methyl, ethyl or propyl.

An acetylide group contains a triple bond —C≡C—R₇, preferably wherein R₇can be hydrogen, an aliphatic, heteroaliphatic, alicyclic,heteroalicyclic, aryl or heteroaryl group as defined above. For thepurposes of the invention when R₇ is alkyl, the triple bond can bepresent at any position along the alkyl chain. In certain embodiments,R₇ is unsubstituted aliphatic, alicyclic or aryl. Preferably R₇ ismethyl, ethyl, propyl or phenyl.

An amino group is preferably —NH₂, —NHR₈ or —N(R₈)₂ wherein R₈ can be analiphatic, heteroaliphatic, alicyclic, heteroalicyclic, a silyl group,aryl or heteroaryl group as defined above. It will be appreciated thatwhen the amino group is N(R₈)₂, each R₈ group can be the same ordifferent. In certain embodiments, each R₈ is independently anunsubstituted aliphatic, alicyclic, silyl or aryl. Preferably R₈ ismethyl, ethyl, propyl, Si(CH₃)₃ or phenyl.

An amido group is preferably —NR₉C(O)R₉ or —C(O)—NR₉(R₉) wherein R₉ canbe hydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic,aryl or heteroaryl group as defined above. In certain embodiments, R₉ isunsubstituted aliphatic, alicyclic or aryl. Preferably R₉ is hydrogen,methyl, ethyl, propyl or phenyl. The amido group may be terminated byhydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic,aryl or heteroaryl group.

An ester group is preferably —OC(O)R₁₀ or —C(O)OR₁₀ wherein R₁₀ can behydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic,aryl or heteroaryl group as defined above. In certain embodiments, R₁₀is unsubstituted aliphatic, alicyclic or aryl. Preferably R₁₀ ishydrogen, methyl, ethyl, propyl or phenyl. The ester group may beterminated by hydrogen, an aliphatic, heteroaliphatic, alicyclic,heteroalicyclic, aryl or heteroaryl group.

An ether group is preferably-OR₁₅ or —R₁₆OR₁₇ wherein R₁₅, R₁₆ and R₁₇can be an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, arylor heteroaryl group as defined above. In certain embodiments, R₁₅, R₁₆and R₁₇ are each unsubstituted aliphatic, alicyclic or aryl. Preferably,R₁₅, R₁₆ and R₁₇ are each methyl, ethyl, propyl or phenyl. The ethergroup may be terminated by hydrogen, an aliphatic, heteroaliphatic,alicyclic, heteroalicyclic, aryl or heteroaryl group.

A sulfoxide is preferably —S(O)R₁₁ and a sulfonyl group is preferably—S(O)₂R₁₁ wherein R₁₁ can be hydrogen, an aliphatic, heteroaliphatic,alicyclic, heteroalicyclic, aryl or heteroaryl group as defined above.In certain embodiments, R₁₁ is unsubstituted aliphatic, alicyclic oraryl. Preferably R₁₁ is hydrogen, methyl, ethyl, propyl or phenyl.

A sulfinate group is preferably —OSOR₁₂ wherein R₁₂ can be hydrogen, analiphatic, heteroaliphatic, haloaliphatic, alicyclic, heteroalicyclic,aryl or heteroaryl group as defined above. In certain embodiments, R₁₂is unsubstituted aliphatic, alicyclic or aryl. Preferably R₁₂ ishydrogen, methyl, ethyl, propyl or phenyl.

Groups R₁₃, R₁₄, R₁₈, R₁₉, R₂₀ and R₂₁ can be a hydrogen an aliphatic,heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl group asdefined above. In certain embodiments, R₁₃, R₁₄, R₁₈, R₁₉, R₂₀ and R₂₁are each unsubstituted aliphatic, alicyclic or aryl. Preferably, R₁₃,R₁₄, R₁₈, R₁₉, R₂₀ and R₂₁ are each hydrogen, methyl, ethyl, propyl orphenyl.

By the term “phosphonium” as used herein is meant the cation comprisingthe formula PH₄+.

Any of the aliphatic (including alkyl, alkenyl, alkynyl, alkylene,alkenylene and alkynylene), heteroaliphatic, (including heteroalkyl,heteroalkenyl, heteroalkynyl, heteroalkylene, heteroalkenylene andheteroalkynylene), alicyclic, carboxylic, carboxylate, cycloalkylene,heteroalicyclic, aryl, arylene, heteroaryl, heteroarylene haloalkyl,alkoxy, aryloxy, alkylthio, arylthio, alkylaryl, silyl, silyl ether,ester, sulfoxide, sulfonyl, imine, acetylide, amino, sulfonate or amidogroups wherever mentioned above, particularly when mentioned asoptionally substituted above may be optionally substituted by halogen,hydroxy, nitro, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy,alkylaryl, amino, amido, imine, nitrile, silyl, silyl ether, ester,sulfoxide, sulfonyl, acetylide, sulfonate or optionally substitutedaliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl orheteroaryl groups (for example, optionally substituted by halogen,hydroxy, nitro, alkoxy, aryloxy, alkylthio, arylthio, amino, imine,nitrile, silyl, sulfoxide, sulfonyl, sulfonate or acetylide).

When we use the term “optionally substituted” at the start of a list ofchemical species we mean that all of the species in the list which canbe substituted may be optionally substituted; that is we do not meanthat only the first species mentioned in the list may be optionallysubstituted.

All of the features contained herein may be combined with any of theabove aspects and in any combination.

Embodiments of the invention will now be described with reference to thefollowing non-limiting examples.

Non-alkylated biphenol ligand precursors used in the following examplesare described in WO2016/012785.

Partially alkylated biphenol ligand precursors used in the followingexamples were prepared using protecting group chemistry in the absenceof a base, as described in WO2016/012785.

The invention will be further illustrated by means of the followingnon-binding examples.

EXPERIMENTAL DESCRIPTION

It should be noted here that the examples given demonstrate the breadthof applicability of the process of the present invention. The yieldsreported in the following examples are substantially unoptimized andreaction conditions have not been extensively tailored to suitindividual target macrocycles. Some of the yields are therefore <40%,but it is understood with variation of the conditions that these yieldscould be substantially improved. In many cases very high yields wereobtained, even without optimisation. It is noted that in each case, andas demonstrated by the enclosed NMR data, no alkylation of the phenolswas observed. The products obtained were the desiredtetra-N-alkylated-diphenol compounds.

Example Set 1: Preparation of Tetra-Benzylated Ligand 2

To a solution of ligand 1 (1.00 g, 1.0 eq) in tetrahydrofuran (10 mL)and acetonitrile (20 mL) were added benzyl bromide (0.96 mL, 4.5 eq) andsodium carbonate (1.05 g, 5.5 eq). The reaction mixture was stirred atreflux for 18 h. After this time, reaction mixture was filtered and thefilter cake was washed with acetonitrile.

The filter cake was solubilised in dichloromethane/water, and phaseswere separated. The aqueous phase was extracted with dichloromethane.The combined organic layers were dried over sodium sulfate, and thesolvents were evaporated in vacuo to yield tetra-benzylated ligand 2(>85%). MS (ESI): 913.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ (ppm) 10.60(s, 2H, phenols), 7.45-7.41 (m, 8H), 7.39-7.34 (m, 8H), 7.31-7.26 (m,4H), 6.89 (s, 4H), 3.75-3.64 (m, 16H), 2.54 (s, 8H), 1.26 (s, 18H), 0.85(s, 12H).

Example Set 2: Preparation of Tetra-Alkylated Ligands 3, 4

Representative procedure: To a solution of ligand 1 (1.00 g, 1.0 eq) intoluene (12 mL) and acetonitrile (24 mL) were added diethylsulfate (1.06mL, 4.5 eq) and sodium carbonate (1.05 g, 5.5 eq). Reaction mixture wasstirred at 85° C. for 2 days. After this time, reaction mixture wasfiltered and the mother liquor was evaporated. The residue wassolubilised in dichloromethane/water, and phases were separated. Theaqueous phase was extracted with dichloromethane. The combined organiclayers were washed with a saturated aqueous solution of sodium hydrogencarbonate, and phases were separated. The organic layer was dried oversodium sulfate, and the solvents were evaporated in vacuo to yieldtetra-alkylated ligand 3 (33%). ¹H NMR (400 MHz, CDCl₃) δ (ppm) 10.68(s, 2H, phenols), 6.95 (s, 4H), 3.63 (s, 8H), 2.55 (q, J=6.9 Hz, 8H),2.37 (s, 8H), 1.26 (s, 18H), 1.07 (t, J=6.9 Hz, 12H), 0.78 (s, 12H). MS(ESI): 665.6 [M+H]⁺ Mass spectrometry data for compound 4 (28%): MS(ESI): 721.6 [M+H]⁺

Example Set 3: Preparation of Tetra-Methylated Ligands 12-19

Representative procedure: To a suspension of ligand 1 (R¹=tBu, R²═H)(1.00 g, 1.0 eq) in acetonitrile (30 mL) were added Me₂SO₄ (0.77 mL, 4.5eq) and sodium carbonate (1.05 g, 5.5 eq). Reaction mixture was stirredat room temperature (RT) for 18 h. After this time, reaction mixture wasfiltered and the filter cake was washed with acetonitrile. The filtercake was solubilised in dichloromethane/water, and phases wereseparated. The aqueous phase was extracted with dichloromethane. Thecombined organic layers were dried over sodium sulfate, and the solventswere evaporated in vacuo to yield tetra-methylated ligand 12 (R=tBu,R²═H>70%) as a white powder. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 10.99 (s,2H, phenols), 6.96 (s, 4H), 3.59 (s, 8H), 2.38 (s, 8H), 2.33 (s, 12H),1.29 (s, 18H), 0.89 (s, 12H). MS (ESI) 609.4 [M+H]⁺

Mass Spectrometry Data for Compounds 13-19:

-   13 (56%) (R¹═SMe, R²═H): MS (ESI) 589.3 [M+H]⁺-   14 (53%) (R¹═Br, R²═H): MS (ESI) 655.2 [M+H]⁺-   15 (52%) (R¹═F, R²═H): MS (ESI) 533.4 [M+H]⁺-   16 (59%) (R¹=SiEt₃, R²═H): MS (ESI) 725.5 [M+H]⁺-   17 (33%) (R¹═OMe, R²═H): MS (ESI) 557.4 [M+H]⁺-   18 (40%) (R¹=nBu, R²═H): MS (ESI) 609.4 [M+H]⁺-   19 (40%) (R¹=Me, R²=Me): MS (ESI) 581.4 [M+H]⁺

Example 4: Preparation of Tetra-Allylated Ligand 20

To a solution of ligand 1 (1.00 g, 1.0 eq) in toluene (10 mL) andacetonitrile (20 mL) were added allyl bromide (0.70 mL, 4.5 eq) andsodium carbonate (1.05 g, 5.5 eq). Reaction mixture was stirred at 50°C. for 6 days. After this time, reaction mixture was filtered and thefilter cake was washed with acetonitrile. The filter cake wassolubilised in dichloromethane/water, and phases were separated. Theaqueous phase was extracted with dichloromethane. The combined organiclayers were dried over sodium sulfate, and the solvents were evaporatedin vacuo to yield tetra-allylated ligand 20 (>90%) as a white powder. MS(ESI) 713.6 [M+H]⁺

Example 5: Further Preparation of Tetra-Methylated Ligand 12

Representative example: To a solution of ligand 1 (1.00 g, 1.0 eq) in2-methyl-tetrahydrofuran (9 mL) and acetone (18 mL) were addeddimethylsulfate (0.77 mL, 4.5 eq) and sodium ethanoate (1.04 g, 7.0 eq).Reaction mixture was stirred at room temperature for 18 h. After thistime, reaction mixture was filtered and the filter cake was washed withacetonitrile. The filter cake was solubilised in dichloromethane/water,and phases were separated. The aqueous phase was extracted withdichloromethane. The combined organic layers were dried over sodiumsulfate, and the solvents were evaporated in vacuo to yieldtetra-methylated ligand 12 (35%).

Examples of Other Bases Used in the Preparation of Ligand 12:

Base=sodium hydroxide (NaOH—5.5 eq),solvent=tetrahydrofuran/acetonitrile (1:3), room temperature, 16 hours.Yield=18%.

Base=disodium phosphate (Na₂HPO₄—5.5 eq),solvent=tetrahydrofuran/acetonitrile (1:3), room temperature, 16 hours.Yield=20%.

Example 6: Preparation of Tetra-Methylated Ligand 22

To a solution of ligand 21 (1.00 g, 1.0 eq) in methanol (30 mL) wereadded dimethylsulfate (0.81 mL, 4.5 eq) and sodium carbonate (1.10 g,5.5 eq). Reaction mixture was stirred at room temperature for 18 h.After this time, reaction mixture was filtered and the mother liquor wasevaporated. The residue was solubilised in dichloromethane/water, andphases were separated. The aqueous phase was extracted withdichloromethane. The combined organic layers were washed with asaturated aqueous solution of sodium hydrogen carbonate, and phases wereseparated. The organic layer was dried over sodium sulfate, and thesolvents were evaporated. 22 (60%); MS (ESI) 581.4 [M+H]⁺

Example 7: Preparation of Tetra-Methylated Ligand 24

To a solution of ligand 23 (1.00 g, 1.0 eq) in dimethyl carbonate (30mL) was added sodium carbonate (1.06 g, 5.0 eq). Reaction mixture wasstirred at reflux for 18 h. After this time, reaction mixture wasfiltered and the mother liquor was evaporated. The residue wassolubilised in dichloromethane/water, and phases were separated. Theaqueous phase was extracted with dichloromethane. The combined organiclayers were washed with a saturated aqueous solution of sodium hydrogencarbonate, and phases were separated. The organic layer was dried oversodium sulfate, and the solvents were evaporated. 24 (45%): MS (ESI)553.4 [M+H]⁺

Example 8: Preparation of Tri-Methylated Ligands 29-32

Representative procedure: To a solution of 25 (0.835 g, 1.4 mmol) in THE(5 mL) and MeCN (10 mL) was added Me₂SO₄ (0.48 mL, 5.0 mmol), followedby Na₂CO₃ (0.690 g, 6.5 mmol). The reaction mixture was stirred at roomtemperature of 18 h. After this time, reaction mixture was filtered andthe filter cake was washed with acetonitrile. The solid collected wassuspended in DCM, washed with H₂O and saturated NaHCO₃, before beingdried over MgSO₄ and reduced in volume to give 29 (70% yield) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ (ppm) 10.92 (br s, 2H, phenol), 7.00 (d, 1H,J=2.5 Hz), 6.99 (d, 1H, J=2.5 Hz), 6.85 (d, 1H, J=2.5 Hz), 6.84 (d, 1H,J=2.5 Hz), 3.65 (s, 2H), 3.62 (s, 2H), 3.42 (s, 2H), 3.41 (s, 2H), 2.56(q, 4H, J=7.0 Hz), 2.40 (s, 2H), 2.37 (s, 2H), 2.33 (s, 3H), 2.33 (s,2H), 2.31 (s, 2H), 2.25 (s, 3H), 2.23 (s, 3H), 1.25 (2×s, 18H), 1.05 (t,3H, J=7.0 Hz), 0.86 (s, 6H), 0.83 (s, 6H). MS (ESI) m/z=623.5 [M+H]⁺.

Data for Compounds 30-32:

-   30 (84%) (R=Bn): MS (ESI) 685.4 [M+H]⁺-   31 (67%) (R=allyl): MS (ESI) 635.5 [M+H]⁺-   32 (73%) (R=p-NO₂—C₆H₅—CH₂): MS (ESI) 730.5 [M+H]⁺

Example 9: Preparation of Tri-Ethylated and Tribenzylated Ligands 34, 35

Representative example: To a solution of 33 (1.501 g, 2.6 mmol) intoluene (5 mL) and MeCN (8 mL) was added Et₂SO₄ (1.2 mL, 9.3 mmol),followed by Na₂CO₃ (1.267 g, 11.9 mmol). The reaction was stirred at 60°C. overnight. The filter cake was collected by filtration and washedwith MeCN. The solid collected was suspended in DCM, washed with H₂O andsaturated NaHCO₃, before being dried over MgSO₄ and reduced in volume togive 34 (65% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ (ppm) 10.80 (br s, 2H, phenol), 6.97 (dd, 4H,J=2.5, 11.6 Hz), 6.86 (dd, 4H, J=2.4, 7.4 Hz), 3.66 (d, 4H, J=7.8 Hz),3.50 (s, 2H), 3.46 (s, 2H), 2.53 (m, 6H), 2.39 (d, 4H, J=7.5 Hz), 2.35(s, 2H), 2.31 (s, 2H), 2.23 (3H, s), 1.25 (18H, d), 1.05 (6H, td. J=1.5,7.0 Hz), 1.01 (t, 3H, J=7.0 Hz), 0.82 (s, 6H), 0.79 (s, 6H). MS (ESI)651.6 [M+H]⁺

Data for compound 35 (74%): As per the representative example, exceptBnBr was used as the alkylating agent and toluene was substituted forTHF. MS (ESI) 837.6 [M+H]⁺

Example 10: Preparation of Di-Ethylated and Di-Benzylated Ligands 38, 39

Representative example: 37 (2.000 g, 3 mmol), BnBr (0.93 mL, 8 mmol),and Na₂CO₃ (1.182 g, 11 mmol) were suspended in MeCN (30 mL) and stirredat 40° C. for 2 days. The reaction mixture was filtered, extracted intoDCM, washed with NaHCO₃ (×3), dried over MgSO₄, and reduced in volume toyield 39 in 75% yield. MS (ESI) 821.6 [M+H]⁺

Data for compound 38 (80%): As per representative example except Et₂SO₄was used as the alkylating agent and the reaction was carried out inTHF/MeCN (1:2). MS (ESI) 697.5 [M+H]⁺.

Example 11: Preparation of Cis-Dimethyl-Dialkylated Ligands 42 and 43

Representative procedure: To a solution of 40 (1 g, 1.6 mmol) in THE (3mL) and MeCN (8 mL) was added Me₂SO₄ (0.34 mL, 3.6 mmol), followed byNa₂CO₃ (0.56 g, 5.3 mmol). The reaction mixture was stirred at roomtemperature overnight. After this time, the reaction mixture wasfiltered and the filter cake was washed with acetonitrile. The solidcollected was suspended in DCM, washed with H₂O and saturated NaHCO₃,before being dried over MgSO₄ and reduced in volume to give 42 (72%yield) as a white solid. MS (ESI) 637.2 [M+H]⁺.

Data for compound 43 (84%), MS (ESI) 761.2 [M+H]⁺.

Attention is directed to all papers and document which are filedconcurrently with or previous to this specification in connection withthis application and which are open to the public inspection with thisspecification, and the contents of all such papers and documents areincorporated herein by reference.

All of the features disclosed in this specification (including anyaccompanying claims, abstract and drawings), and/or all of the steps ofany method or process so disclosed, may be combined in any combination,expect combinations where at least some of such features and/or stepsare mutually exclusive.

Each feature disclosed in this specification (including any accompanyingclaims, abstract and drawings) may be replaced by alternative featuresserving the same, equivalent or similar purpose, unless expressly statedotherwise. Thus, unless expressly stated otherwise, each featuredisclosed is one example only of a generic series of equivalent orsimilar features.

The invention is not restricted to the details of the foregoingembodiment(s). The invention extends to any novel one, or any novelcombination, of the features disclosed in this specification (includingany accompanying claims, abstract or drawings), or to any novel one, orany novel combinations, of the steps of any method or process sodisclosed.

What is claimed is:
 1. A process for preparing a tetra-substitutedaminobiphenol macrocyclic ligand having a structure (1), comprising thestep of treating a precursor compound having a structure (II) with acompound having a structure R₆-L where L represents a leaving group(hereinafter compound (III)) in the presence of a base;

wherein R₁ and R₂ are independently selected from hydrogen, halide, anitro group, a nitrile group, an imine group, —NCR₁₃R₁₄, an amine, anether group —OR₁₅ or —R₁₆OR₁₇, an ester group —OC(O)R₁₀ or —C(O)OR₁₀, anamido group —NR₉C(O)R₉ or —C(O)—NR₉(R₉), —COOH, —C(O)R₁₅,—OP(O)(OR₁₈)(OR₁₉), —P(O)R₂₀R₂₁, a silyl group, a silyl ether group, asulfoxide group, a sulfonyl group, a sulfinate group or an acetylidegroup or an optionally substituted alkyl, alkenyl, alkynyl, haloalkyl,aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, alicyclic orheteroalicyclic group; R₃ is independently selected from2,2-dimethylpropane-1,3-diyl, ethane-1,2-diyl,2,2-fluoropropane-1,3-diyl, propane-1,3-diyl, phenylene,cyclohexane-1,4-diyl cyclohexane-1,2-diyl or biphenylene; R₄ isindependently selected from hydrogen, or optionally substitutedaliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl,heteroaryl, alkylheteroaryl or alkylaryl; R₅ is independently selectedfrom hydrogen, optionally substituted aliphatic, heteroaliphatic,alicyclic, alkanoate, acrylate, carboxyl, heteroalicyclic, aryl,heteroaryl, alkylheteroaryl or alkylaryl, or two R₅ species may togetherbe selected from optionally substituted alkylene, alkenylene oralkynylene, bonded to two different N groups of the compound ofstructure (II), with the proviso that at least one of the species R₅ ishydrogen; and E is independently selected from NR₅ and NR₆, with theproviso that at least one of the species E is NR₆; wherein R₆ isindependently selected from optionally substituted aliphatic, alicyclic,heteroalicyclic, aryl, heteroaryl, ether, polyether, or optionallysubstituted alkylaryl or alkylheteroaryl; wherein R₉, R₁₀, R₁₃, R₁₄,R₁₈, R₁₉, R₂₀ and R₂₁ are independently selected from hydrogen or anoptionally substituted aliphatic, heteroaliphatic, alicyclic,heteroalicyclic, aryl or heteroaryl group and R₁₅, R₁₆ and R₁₇ areindependently selected from an optionally substituted aliphatic,heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl group;and wherein the molar ratio of compound (III) to the number of NH sitesin the compound of structure (II) is at least 0.6.
 2. The process ofclaim 1, wherein the molar ratio of the compound having the structure(III) to the number of NH sites in the macrocycle is at least 0.8. 3.The process of claim 2, wherein the molar ratio of the compound havingthe structure (III) to the number of NH sites in the macrocycle (II) isat least
 1. 4. The process of claim 3, wherein the molar ratio of thecompound having the structure (III) to the number of NH sites in themacrocycle (II) is at least 1.1.
 5. The process of claim 1, wherein R₁and R₂ are independently selected from hydrogen, halide, amino, nitro,sulfoxide, sulfonyl, sulfinate, silyl, silyl ether and an optionallysubstituted alkyl, alkenyl, aryl, heteroaryl, heteroalicyclic, alkoxy,aryloxy or alkylthio or arylthio.
 6. The process of claim 5, wherein R₂is hydrogen or alkyl and R₁ is independently selected from hydrogen,C₁₋₆alkyl, C₁₋₆haloalkyl, alkoxy, aryl, halide, nitro, sulfonyl, silylor alkylthio.
 7. The process of claim 6, wherein R₂ is hydrogen and R₁is independently selected from t-butyl, n-butyl, i-propyl, methyl,piperidinyl, methoxy, hexyl methyl ether, —SCH₃, —S(C₆H₅), H, nitro,trimethylsilyl, triethylsilyl, methylsulfonyl (—SO₂CH₃), triethylsilyl,halogen or phenyl.
 8. The process of claim 1 wherein R₄ is independentlyselected from hydrogen, and optionally substituted aliphatic or aryl. 9.The process of claim 8, wherein R₄ is independently selected fromhydrogen, and optionally substituted alkyl or aryl.
 10. The process ofclaim 8, wherein R₄ groups are selected from hydrogen, methyl, ethyl,n-propyl, n-butyl, phenyl and trifluoromethyl.
 11. The process of claim1, wherein R₅ is independently selected from hydrogen, optionallysubstituted alkyl which is optionally interrupted by at least one Natom, or by at least one O atom, or by at least one S atom, optionallysubstituted alkylthio, alkylaryl, alkylheteroaryl, alkenyl, alkynyl,heteroalkenyl, heteroalkynyl, aryl, alicyclic, heteroalicyclic,heteroaryl, sulfonate, alkanoate (—C(O)—OR₁₀), acrylate (arylC(O)O—),aryl-C(O)OR₁₀, alkylaryl-C(O)OR₁₀, alkyl-C(O)—OR₁₀, carbonyl(—C(O)—R₁₀), ether, polyether, alkylarylC(O)O— or carboxyl; or two R₅groups together comprise an optionally substituted alkylene group bondedto two different N groups on the same macrocycle; wherein at least onespecies R₅ is hydrogen.
 12. The process of claim 11, wherein R₅ isindependently selected from optionally substituted alkyl, alkylaryl,alkenyl, alkynyl, sulfonate, alkanoate, aryl-C(O)OR₁₀,alkylaryl-C(O)OR₁₀, alkyl-C(O)—OR₁₀ or alkyl-C≡N.
 13. The process ofclaim 12, wherein R₅ is independently selected from methyl, ethyl,propyl, butyl, allyl, propargyl, benzyl, 4-nitrobenzyl,—CH₂CH₂—C(O)—OR₁₀, —CH₂CH₂—C≡N, or —C(1-4)alkylC(O)O—, or benzoate whichis unsubstituted or ring-substituted by 1, 2 or 3 C(1-4)alkyl groups.14. The process of claim 11, wherein one species R₅ is hydrogen and theremaining three species R₅ are independently selected from thesubstituent group.
 15. The process of claim 11 wherein two species R₅are hydrogen and the remaining two species R₅ are independently selectedfrom the substituent.
 16. The process of claim 11, wherein three speciesR₅ are hydrogen and the remaining one species R₅ is independentlyselected from the substituent group.
 17. The process of claim 11 whereinall four R₅ species are hydrogen.
 18. The process of claim 1, wherein R₆is independently selected from optionally substituted alkyl, alicyclic,alkenyl, alkynyl, alkylaryl, methylpyridine, ether, polyethylene glycol,or polypropylene glycol.
 19. The process of claim 18 wherein R₆ isindependently selected from a optionally substituted C(1-10)alkyl group,a C(1-10)alkenyl group or a C(1-10)alkynyl group.
 20. The process ofclaim 18, wherein R₆ is independently selected from C(1-10)alkyl, allyl,propargyl or benzyl.
 21. The process of claim 1, wherein the compoundR₆-L has a leaving group L which is selected from halogen, or an ethergroup, or a tertiary amine, or a sulfonate group of formula —O—SO₂—R_(x)where R_(x) is selected from optionally substituted aliphatic or aryl oralkylaryl (including polymer-bound sulfonate groups); or a group offormula —O—SO₂—O—R_(y) or —O—CO—O—R_(y) where R_(y) representsoptionally substituted aliphatic or aryl or alkylaryl.
 22. The processof claim 21, wherein the leaving group L is a chlorine, bromine ofiodine atom or a group of formula R_(y)—O—SO₂—O— or R_(y)—O—CO—O— whereboth species R_(y) are C₍₁₋₄₎ alkyl groups or an alkyl sulfonate, arylsulfonate, halo sulfonate or trihaloalkyl sulfonate.
 23. The process ofclaim 1, wherein the base for use in the process is an inorganic baseselected from carbonates, hydrogen carbonates, alkanoates, hydroxides,silicates, phosphates and borates of Group I and Group II metals, orfrom an organic base selected from tertiary amine bases.
 24. The processof claim 23, wherein a base is selected from sodium carbonate, potassiumcarbonate, cesium carbonate, cesium carbonate, magnesium carbonate,calcium carbonate, ammonium carbonate, sodium hydroxide, potassiumhydroxide, magnesium hydroxide, calcium hydroxide, ammonium hydroxide,sodium (C1-10) alkanoates, potassium (C1-10) alkanoates, sodiummetasilicate, potassium metasilicate, sodium borate, potassium borate,trisodium phosphate, disodium phosphate, monosodium phosphate,monopotassium phosphate, dipotassium phosphate or tripotassiumphosphate.
 25. The process of claim 1, wherein a compound of structure(I) is prepared.
 26. A compound of structure (Ie)

wherein R₁ and R₂ are independently selected from hydrogen, halide, anitro group, a nitrile group, an imine group, —NCR₁₃R₁₄, an amine, anether group —OR₁₅ or —R₁₆OR₁₇, an ester group —OC(O)R₁₀ or —C(O)OR₁₀, anamido group —NR₉C(O)R₉ or —C(O)—NR₉(R₉), —COOH, —C(O)R₁₅,—OP(O)(OR₁₈)(OR₁₉), —P(O)R₂₀R₂₁, a silyl group, a silyl ether group, asulfoxide group, a sulfonyl group, a sulfinate group or an acetylidegroup or an optionally substituted alkyl, alkenyl, alkynyl, haloalkyl,aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, alicyclic orheteroalicyclic group; R₃ is independently selected from2,2-dimethylpropane-1,3-diyl, ethane-1,2-diyl,2,2-fluoropropane-1,3-diyl, 2,2-propane-1,3-diyl, phenylene,cyclohexane-1,4-diyl cyclohexane-1,2-diyl or biphenylene; R₄ isindependently selected from hydrogen, or optionally substitutedaliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl,heteroaryl, alkylheteroaryl or alkylaryl; and E is independentlyselected from NR₅ and NR₆, wherein R₅ is independently selected fromoptionally substituted aliphatic, heteroaliphatic, alicyclic, alkanoate,acrylate, carboxyl, heteroalicyclic, aryl, heteroaryl, alkylheteroarylor alkylaryl; or two R₅ species may together be selected from optionallysubstituted alkylene, alkenylene or alkynylene, bonded to two differentN groups of the compound of structure (II); wherein R₆ is independentlyselected from optionally substituted aliphatic, alicyclic,heteroalicyclic, aryl, heteroaryl, ether, polyether, or optionallysubstituted alkylaryl or alkylheteroaryl; with the first proviso that atleast one of the species E is conforms to the definition given for NR₆;and with the second proviso that the groups R₅ and R₆ are not allidentical with each other; wherein R₉, R₁₀, R₁₃, R₁₄, R₁₈, R₁₉, R₂₀ andR₂₁ are independently selected from hydrogen or an optionallysubstituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, arylor heteroaryl group and R₁₅, R₁₆ and R₁₇ are independently selected froman optionally substituted aliphatic, heteroaliphatic, alicyclic,heteroalicyclic, aryl or heteroaryl group.
 27. The process of claim 21wherein the optionally substituted aliphatic or aryl or alkylarylincludes polymer-bound sulfonate groups.